This application proposes a career development plan for Dr. A. Cortney Henderson. As a postdoctoral fellow working with Dr. Kim Prisk (mentor), she studied the effects of lung water and gravity on the distribution of pulmonary blood flow using MRI. During the remainder of her postdoctoral training, she will learn how to apply the multiple inert gas elimination technique (MIGET) in chronic obstructive pulmonary disease (COPD) patients under Dr. Peter Wagner (co-mentor). The research environment at UCSD is excellent, and the Division of Physiology under the leadership of Dr. John West and Dr. Peter Wagner has been among the best in the world for over 30 years. The proposed research plan will study physiological mechanisms associated with the gas exchange defects in COPD, which is characterized by ventilation-perfusion ratio (VA/Q) inequality. Hypoxic pulmonary vasoconstriction (HPV) reduces VA/Q mismatch in COPD. The overall hypothesis is that differing overall VA/Q inequalities, spatial patterns of ventilation and blood flow, and effects of HPV on the distribution of blood flow in COPD reflect whether the disease is predominantly emphysema (lung tissue destruction) or predominantly airway disease. The spatial distribution of pulmonary blood flow, ventilation, and VA/Q will be measured using MRI and overall VA/Q inequality measured using MIGET. COPD patients presenting with predominantly emphysema or predominantly airway disease and age-matched healthy subjects will be studied while breathing air and then a hyperoxic gas to alleviate HPV. The following key hypotheses will be tested: (1) in emphysema predominant patients, the primary cause of regions of high VA/Q is low perfusion due to lung tissue and capillary destruction, the spatial distribution of which is an important determinant of the heterogeneity of ventilation and blood flow, (2) in airway disease predominant patients, the primary cause of regions of low VA/Q is low ventilation due to bronchial obstruction, and (3) the spatial pattern of HPV is an important mechanism contributing to the type of overall VA/Q inequality and spatial heterogeneity of blood flow. We will collaborate with Joe Ramsdell, M.D., UCSD Clinical Study Center PI for the multi-center Genetic Epidemiology of COPD (COPDGene) project funded by NIH, providing access to a large number of well-characterized COPD patients. The overall goal of the COPDGene study is to identify the genetic risk factors in COPD. The aims of COPDGene are highly synergistic with this proposal, thus allowing for characterization of the subtypes of COPD based on physiological mechanisms. RELEVANCE (See instructions): COPD is the 4th leading cause of death worldwide, and will be the 3rd leading cause of death by 2020. Combined use of MIGET and MRI to address the proposed hypotheses for a well-characterized group of COPD patients participating in the NIH-funded COPDGene study will provide insight into the underlying physiology in the subtypes of COPD, and therefore may facilitate optimal patient selection for current medical treatments as well as provide pathways for future therapies.